Just take a break - relax. We humans like to do that. One might even be inclined to say that it is in our nature. If you take a closer look at the basis of our existence, the cells, then this idea is actually pretty close to molecular reality. The cells also take a break under certain circumstances or stop dividing. This state is called cellular senescence.
Colloquially, these cells are often referred to as “undead” or “zombie cells“ And that is pretty close to the truth, because senescent cells are neither dead nor truly aliveWe will be dealing with this relatively new scientific discovery in two articles. In the article about senolytics we show you the scientific background and give you tips from science on how to get rid of senescent cells. This article is about more about senescence and its role as one of the molecular Hallmarks of Aging.
Hayflick limit and telomeres – how do the “undead” arise?
Senescence (from Latin Senescere; aging) plays an important role as the final stage of some processes in the body. In the previous articles on genomic instability and to mitochondrial dysfunction we have already learned about senescence. At a young age, senescence seems to be a kind of safe intermediate state for degenerated cells.
Cellular senescence is fundamentally a stable arrest of the cell cycle. The first discoveries in this direction were made in the early 1960s by the scientists Leonard Hayflick and Paul Moorhead. They found that human fibroblasts (connective tissue cells) in a culture divide a maximum of about 50 timesbefore they suddenly stop and age.
What is common practice today was groundbreaking back then. In those days long gone, the prevailing view in cell biology was that all cultured cells were immortal. Hayflick overthrew this dogma with his experiments and found that only cancer cells have this characteristic. The phenomenon of the upper limit of division is called replicative senescence, or after its discoverer: Hayflick limit.
We now know that the senescence observed by Hayflick is caused by telomere shortening But there are also other stimuli, apart from telomere attrition, that can trigger cellular senescence.
How do you measure senescence?
In addition to damage to the telomeres, two further points on cellular senescence in: non-telomeric DNA damage and the INK4/ARF locus on the DNA. Both occur in connection with chronological aging and can induce senescence - this has been proven in experiments. But how do you actually prove something like that?
First of all, it is important to note that Senescence is not directly measurable.There is no laboratory parameter that spits out a concrete value after a blood sample is taken. Therefore, researchers use so-called replacement markers, which indirectly allow a conclusion. In the case of cellular senescence, DNA damage or the senescence-associated β-galactosidase (SABG).
In one study from 2009 A quantification was carried out in mice using these two parameters. The values obtained were approximately 8% senescent cells in young mice and about 17% in very old mice. Looking at the values by organ, similar values were found in the skin, lungs and spleen. The researchers observed no changes in the heart, kidneys or muscle tissue.
This is exciting because it means that the The extent of cellular senescence varies from tissue to tissueIn the case of tumor cells, for example, there is experimental evidence that they are subject to strict immune surveillance and can subsequently be efficiently removed.
Aging and Cellular Senescence
We now know that the amount of senescent cells increases with age. This observation has been made in numerous studies. Why is this so? Without going into too much detail, there is a simple answer. too many of these "undead" cells or it will be too few minedThe truth lies somewhere in the middle. But it would be too short-sighted to say that aging research now has a new enemy. The connection is not as linear as it seems at first glance.
Perhaps the main purpose of senescence is something else entirely. preventing the proliferation of damaged cells and the triggering of the clearance by the immune system. Recall that DNA damage is a surrogate marker used to quantify senescence. Senescence is, among other things, a advantageous compensatory reactionto free tissue from damaged and possibly even tumorous cells.
The prerequisite for this, however, is an effective cell replacement system. The senescent cells must first be removed and then replaced so that homeostasis or balance in the tissue is maintained. This is exactly where the catch is with regard to aging.
This The turnover system has a tendency to become inefficient with increasing age, which is reflected in a reflects the lack of regenerative capacity of cellsThis leads to an accumulation of senescent cells, which sooner or later worsen the damage and intensify aging. However, the mere presence of a constantly increasing number of inactive cells is not the decisive factor. Rather, the secretome the evildoer.
Secretome sounds mysterious at first, but it is “only” the totality of all secreted substances of a cell. In the case of senescent cells, the secretome is particularly rich in inflammatory and destructive substances. In science it is called Senescence-Associated Secretory Phenotype (SASP).You can find out why exactly these inflammatory substances can cause problems in our article on Inflammaging.
Cell division as a recycling mechanism is strictly regulated in the body.
Mitogenic signaling – when something goes wrong during cell division
In addition to DNA damage, excessive mitogenic (cell division inducing) signal transmission associated with senescence. Mitogen can be thought of as MITOse GENEeasier to remember. Mitosis is the process of cell division. There are a whole lot of these mitogenic or oncogenic (cancer-causing) changes. In response to these signals, senescence can be triggered in the cellThere are also a number of mechanisms for this, INK4a / ARF locus but is unsurpassed in significance.
INK4a / ARF locus and p53 – what is hidden behind the abbreviations?
Don’t be alarmed, the topic is not nearly as complicated as the title suggests. The extent of p16INK4a (the protein produced based on the INK4a gene) is associated with chronological age in all tissues analyzed, both in mice and humans. This colossal relevance is remarkable. The INK4a/ARF locus (location on the DNA) was identified in a meta-analysis (highest scientific evidence) as the genomic locus that is associated with the highest number of age-associated pathologies.
These include various types of cardiovascular diseases, diabetes, glaucoma and Alzheimer's disease. p53 is another protein that induces senescence. “p” in the nomenclature always stands for protein.
Did you know? The protein p16Ink4a is also detectable in senescent liver cells. An accumulation of these “zombie” cells over time contributes to the activation pro-inflammatory signals from the cells, also known as the Senescence-Associated Secretory Phenotype (SASP), which can lead to increased inflammation and increased accumulation of fat in the liver. This process is often associated with non-alcoholic fatty liver disease (NAFLD).
Japanese pagoda tree as a potent source of quercetin: Quercesome is 20 times more bioavailable than conventional quercetin powder due to phospholipids.
Opposite, but still the same?
Due to the senescence-inducing function of p16INK4a and p53, researchers put forward the obvious hypothesis that the two proteins contribute to physiological agingThe age-promoting effect is therefore negligible when one considers the much more important benefits in tumor suppression. In reality, however, the issue is somewhat more complicated, which conflicting research results suggest.
In mice that had aged prematurely due to extensive and persistent cell damage achieved elimination of p16INK4a and p53 an improvement in the overall function of the organismIn another experiment, mice with a slight increase in the two proteins had a longer lifespan. This survival advantage was greater than would be expected from a lower incidence of cancer.
The activation of the two proteins mentioned is therefore a beneficial reaction with regard to the development of tumors and thus cancer. This prevents the spread of mutated cells. However, if damage is widespread and affects a large proportion of our body’s cells, then the body can no longer keep up: the regenerative capacity is exhausted. Under these conditions, the activation of INK4a / ARF is detrimental and aging is accelerated.
Cellular Senescence – Conclusion
Cellular senescence is a useful compensatory response to damage, but can also accelerate aging and be detrimental to health if tissues are no longer able to recover sufficiently. Ultimately, studies have shown that there are two contradictory intervention approaches, both of which can contribute to longevity to date.
On the one hand, a tumor suppressor effect positive effects on aging. On the other hand, the elimination of senescent cells in experiments a delay of age-related diseases. So the “undead” are not completely useless.
Presumably it is as always in nature. In the right balance, senescent cells are beneficial for our health, as they help us, for example, to freeze damaged cells so that they do not degenerate further. On the other hand, the number of senescent cells can increase so much with age and thus also the inflammationsthat age-related diseases are promoted.
The next article in this series is about the eighth hallmark of aging: stem cell exhaustion.
